This invention relates to cubic liquid crystalline compositions, precursors thereof, and methods for their preparation. More particularly, this invention relates to improved methods for preparing dispersions of cubic liquid crystalline gel particles.
xe2x80x9cAmphiphilic substancexe2x80x9d means a molecule with both hydrophilic and hydrophobic (lipophilic) groups. Amphiphilic substances spontaneously self-associate in aqueous systems forming various types of aggregates. Examples of these aggregates include lamellar phases, hexagonal phases, and cubic phases. These phases are thermodynamically stable. The long-range order in these phases, in combination with liquid-like properties in the short-range order, gave rise to the notation xe2x80x9cliquid crystalline phasesxe2x80x9d.
Liquid crystalline phases (i.e., bulk cubic liquid crystalline gels and dispersions of cubic liquid crystalline gel particles) can be formed from precursors including an amphiphilic molecule such as a lipid and a polar liquid. The cubic liquid crystalline gel phase structures can form in response to some event, such as a temperature change or dilution of the precursor. In some applications, a cubic gel precursor forms a bulk cubic liquid crystalline gel only when needed for the specific application. For example, precursors have been used in antiperspirants, in which a water-insoluble liquid crystalline phase forms when the precursor contacts sweat (salt water). The resulting bulk liquid crystalline gel has a cubic or hexagonal liquid crystal structure that blocks pores.
Precursors have also been used to deliver a therapeutic agent to treat periodontal disease, for example, by putting the precursor comprising a monoglyceride and an active ingredient into a reservoir such as a periodontal pocket. The precursor forms bulk cubic liquid crystalline gel on contact with saliva and then provides controlled release of the therapeutic agent.
However, in these applications, some uncontrolled stimulus (such as sweating or salivating) is always required for the precursor to form bulk cubic liquid crystalline gel. No control can be exercised over the properties of the bulk cubic liquid crystalline gel formed. Furthermore, particulate cubic liquid crystalline gel cannot be formed directly from the precursor. Therefore, it is an object of this invention to provide precursors that can directly form either bulk or particulate cubic liquid crystalline gels. It is a further object of this invention to provide a method for using the precursor to prepare bulk and particulate cubic liquid crystalline gels with controlled properties.
The liquid crystalline phases have distinct hydrophilic and hydrophobic domains, which give them the ability to dissolve (solubilize) or disperse water-soluble, oil-soluble, and amphiphilic compounds. Liquid crystalline phases are highly ordered structures that restrict the diffusion of added ingredients, thereby making them useful for controlled-release purposes. Cubic liquid crystalline phases can be prepared as pastes and thus are particularly useful as delivery vehicles due to their rheological properties. Cubic liquid crystalline phases are also advantageous in that they are mechanically robust and resistant to physical degradation.
Bulk cubic liquid crystalline gels prepared in advance (i.e., before administration rather than in situ, as in the treatment of periodontal disease described above) can also be used as controlled release reservoirs of pharmaceutical materials. However, bulk cubic liquid crystalline gels are typically difficult to prepare due to the properties of the raw materials and rheological properties of the gels themselves. Lipids that yield cubic liquid crystalline phases, such as monoglycerides, are typically waxy solids at room temperature. Therefore, the bulk cubic liquid crystalline gel is prepared by equilibrating at high temperature or over many hours, or both, because transport of water is slow through solid lipids. Processes that require long hold times at high temperatures to manufacture bulk cubic liquid crystalline gels are not economically practical, particularly on a commercial scale. Therefore, it is a further object of this invention to provide a method for forming a bulk cubic liquid crystalline gel at relatively low temperature (e.g., room temperature) and in a relatively short amount of time (e.g., within minutes). It is a further object of this invention to provide an economical and practical method for preparing commercial scale quantities of bulk cubic liquid crystalline gels.
Bulk cubic liquid crystalline phases are high-viscosity solid-like gels, which makes large-scale processing to form dispersed particles of cubic liquid crystalline phase difficult. Large scale processing of bulk solid and solid-like materials is difficult because of problems associated with adequate mixing and homogenizing. High energy input is required, and this energy can degrade liquid crystalline structures. For example, high energy input processes, such as those employing high shear can physically degrade crystalline structures. High energy input processes, such as those employing high temperatures can chemically degrade the compounds making up the liquid crystalline structures. Furthermore, high energy input processes are costly and require more precise control and maintenance. Therefore, it is an object of this invention to provide methods for preparing cubic liquid crystalline phase materials that are less costly and more efficient than the methods involving bulk solid processing.
Lamellar phases have a bilayer sheet structure. When a lamellar phase is dispersed in excess water, the lamellar phase forms vesicles and liposomes. xe2x80x9cVesiclexe2x80x9d means an enclosed shell comprised of one bilayer of amphiphilic molecules. xe2x80x9cLiposomexe2x80x9d means an enclosed shell comprised of more than one bilayer of amphiphilic molecules. Vesicles and liposomes can be spheroidal, ellipsoidal, or irregularly shaped; however, spheroidal shells are the most stable.
Vesicles and liposomes suffer from the drawback that they are non-equilibrium states, which means that, inevitably, they will degrade. Furthermore, vesicles and liposomes are relatively expensive to manufacture. Therefore, it is an object of this invention to provide a stable, less expensive alternative to vesicles and liposomes.
Bulk cubic liquid crystalline gel can also be dispersed to form particles. Dispersed particles of cubic liquid crystalline phases are structurally distinct from vesicles and liposomes. Dispersed cubic gel particles have a cubic or spherical outer structure with a bicontinuous cubic internal structure. The bicontinuous cubic internal structure has distinct hydrophilic and lipophilic domains, and is described in S. Hyde et al., The Language of Shape, Elsevier, Amsterdam, 1997, chapters 1 and 4.
Typically, cubic liquid crystalline gel particles are formed via fragmentation and dispersion of homogeneous bulk cubic liquid crystalline gel. Fragmentation is carried out in combination with a fragmentation agent such as polysaccharides, proteins, amphiphilic macromolecules and lipids, amphiphilic polymers, and amphiphilic compounds. Fragmentation also requires the use of a high energy input process by, for example, high shear milling or sonication.
Fragmenting and dispersing solid and solid-like materials, such as bulk cubic liquid crystalline gel, are difficult and impractical above very small processing scales (e.g., on the order of several grams, or less) without significant energy input and hold time. This makes commercial scale production of dispersed cubic gels expensive and impractical. Furthermore, high energy input processes can create non-equilibrium structures, such as vesicles and liposomes. Therefore, it is an object of this invention to develop a means for producing dispersed cubic liquid crystalline gel particles that does not require a fragmentation step. It is a further object of this invention to provide a method for forming cubic gel particles instantaneously by homogeneous nucleation upon dilution. It is a further object of this invention to provide an economical and practical method for preparing commercial scale quantities of cubic liquid crystalline gel particle dispersions.
It has been surprisingly found that cubic liquid crystalline phase gels can be prepared in the presence of a hydrotrope. (Hydrotropes are perversely well-known for their efficiency at disrupting liquid crystalline materials, see Pearson, J. T., Smith, J. M., xe2x80x9cThe Effect of Hydrotropic Salts on the Stability of Liquid Crystalline Systems,xe2x80x9d J. Pharm. Pharmac., 26, 123-124 (1974).) This invention relates to compositions that can be in the form of a cubic gel precursor, a bulk cubic liquid crystalline gel, or a dispersion of cubic liquid crystalline gel particles. The precursor comprises: (A) a hydrotrope and (B) an amphiphile that is capable of forming cubic liquid crystalline phase structures. The bulk cubic liquid crystalline gel comprises ingredients (A), (B) and (C) a solvent. The dispersed cubic liquid crystalline gel particles comprise ingredients (A), (B), (C), and preferably (D) a stabilizer. This invention further relates to methods for preparing the above compositions. The methods of this invention are commercially advantageous in that bulk solids handling of ingredient (B) can be eliminated when ingredient (B) is a solid at room temperature, and the fragmentation step required by methods for dispersing bulk liquid crystalline materials to form dispersions of particles having liquid crystalline structures can be eliminated by preparing dispersions of cubic gel particles directly from the cubic gel precursor.